Diuretics are one of the most widely prescribed drugs, yet there has been little innovation for decades. Patients with congestive heart failure (CHF) often have chronic kidney disease (CKD) and retain Na+ and fluid, which causes pulmonary congestion and troublesome lower limb edema. Most of these 7 million patients are treated with the loop diuretic furosemide despite its many limitations. These include low and highly variable bioavailability, frequent hypokalemia, reduction in glomerular filtration rate (GFR and very short duration of action (approximately 3 hours) which permits the kidney to regain much of the salt and water lost in between doses. Therefore, it is not surprising that many patients become furosemide resistant (i.e. retain fluid despite furosemide therapy). This is a frequent cause for hospital readmission and a cause of dangerous complications such as bronchopneumonia. To address these manifest deficiencies of furosemide therapy, we have developed an extended release (ER) formulation of the best in class potassium-neutral loop diuretic torsemide that releases the drug over 8-10 hours. A completed randomized, double cross-over phase I study, funded by a phase 1 SBIR grant, compared the responses of 10 healthy subjects consuming a fixed, high Na+ intake (300 mmol*day-1) to one 20 mg dose of either immediate release (IR) torsemide or ER torsemide (separated by a 3 week washout period). Torsemide ER caused twice as much loss of fluid and Na+ and reduction in body weight and BP and half as much fall in GFR. The present phase II SBIR grant test the hypothesis that torsemide ER will cause a more rapid and complete correction of edema (from measurements of lower limb edema) as compared to furosemide IR in patients with CHF +/- CKD. Patients with CHF (+/- CKD) and residual edema despite ongoing furosemide therapy will enter a phase IIb/III double blinded, double-placebo randomized clinical trial comparing torsemide ER to furosemide IR. The primary endpoint will be reduction in edema, measured by water displacement by the lower limbs over one week. Secondary and additional endpoints will include changes in body weight, plasma volume (from hematocrit), cardiac stretch (from brain natriuretic hormone), neurohormonal activation and quality of life. Based on our study in healthy subjects, we anticipate that torsemide ER will cause a more complete correction of edema and reduction in volume overload. The data generated should be sufficient to register torsemide ER with the FDA to market it with a superiority label over furosemide. Torsemide ER would improve diuretic therapy and thereby address an unmet need to keep patients with edema free of recurrent congestion and repeated hospital readmissions.